Summary The temporomandibular joint (TMJ) is a complex joint system critical for dental occlusion, mastication, respiration and speech. The TMJ is comprised of a network of muscles, ligaments, and a fibrocartilaginous disc and condyle. TMJ trauma and degenerative diseases, including TMJ osteoarthritis (OA), are debilitating and compromise quality of life. TMJ diseases afflict over 10 million Americans at an annual cost of ~$4 billion and are one of NIDCR?s research priorities. Current treatments for TMJ OA are typically two-fold extremes, involving either pain management or invasive surgeries, including total joint replacements with high failure rates. There is a paucity of minimally invasive and directed TMJ therapies that target pathological mechanisms and promote innate tissue regeneration. One barrier preventing the development of targeted TMJ regenerative therapies is the deficient knowledge underlying the role of stem cells in TMJ health and disease. Exploiting the regenerative capabilities of resident stem cells to repair TMJ tissues represents a minimally invasive stem cell-based treatment for TMJ OA. We have identified TMJ fibrocartilage stem cells (FCSCs) that reside in the TMJ condyle superficial zone. Over-active Wnt/?Catenin deplete FCSCs and cause TMJ OA in mice, rabbits and humans. We showed blocking Wnt via weekly TMJ intra-articular injections of the Wnt inhibitor sclerostin ameliorated TMJ OA in a rabbit TMJ injury model. Thus therapeutic application of exogenous sclerostin maintains the pool of FCSCs and repairs TMJ. These data suggest that sclerostin mediated Wnt/?Catenin inhibition in FCSCs represents a stem cell-based therapeutic strategy for TMJ regeneration. However, a pharmacological drug delivery system for bench-side sclerostin administration in human TMJ OA patients has not been defined. Based on our preliminary data, we hypothesize that delivery of injectable, sustained release sclerostin in HA hydrogel will target resident TMJ fibrocartilage stem cells to regenerate TMJ. We will develop sustained release sclerostin therapy for Wnt inhibition in FCSCs by encapsulating sclerostin in HA hydrogel. We will use an established rabbit TMJ injury model to demonstrate injectable sustained release sclerostin as a therapeutic regenerative strategy for TMJ OA. Our long-term goal is to develop a minimally invasive TMJ regenerative therapy through targeted, drug-based modulation of resident TMJ fibrocartilage stem cells. Specific Aim 1: Develop injectable hyaluronic acid sustained release sclerostin hydrogel to inhibit Wnt/?Catenin and promote chondrogenic differentiation in TMJ fibrocartilage stem cells. Specific Aim 2: Determine the efficacy of injectable hyaluronic acid sustained release sclerostin to ameliorate TMJ osteoarthritis.